OBJECTIVES: To compare the efficacy of treatments in moderate-to-severe rheumatoid arthritis (RA) in biologic-naïve patients with inadequate response to conventional disease modifying antirheumatic drugs (cDMARDs). METHODS: MEDLINE, Embase, and Cochrane Central Register were searched for RCTs published in 01/1990 to 08/2016. Treatments included were tumor necrosis factor inhibitors (TNFis; etanercept, adalimumab, infliximab, certolizumab pegol, golimumab), rituximab, abatacept, Interleukin 6 inhibitors (tocilizumab, sarilumab), and Janus kinase inhibitors (tofacitinib and baricitinib), each combined with cDMARDs. Outcomes were difference in mean change in modified Total Sharp Scores (mTSS) between each regimen and cDMARDs, and probabilities of ≥20% improvement in the American College of Rheumatology response criteria (ACR20), at 6-months and 12-months. A Bayesian network meta-analysis using random-effects models estimated the comparative efficacy for these regimens. RESULTS: Up to 72 studies were included in this analysis. At 6-months, the difference in mean change in mTSS (95%CrI) versus cDMARDs ranged from -1.01(-3.70;1.69) for adalimumab to -3.74(-8.07;0.62) for infliximab in TNFis; and from -0.36(-2.80;2.04) for tofacitinib to -1.08 (-3.21;1.01) for tocilizumab in non-TNFis. At 6-months only the etanercept regimen had statistically significant difference in mean mTSS change -2.08(-3.67;-0.52) vs. cDMARDs. At 6-months, ACR20 (95%CrI) in TNFis ranged from 58.8%(47.8%;69.8%) for infliximab to 74.3%(66.2%;81.1%) for certolizumab pegol; and from 52.8%(33.5%;71.7%) for baricitinib to 63.3%(45.1%;80.0%) for sarilumab in non-TNFis. At 12-months, differences in mean change in mTSS ranged from –2.15(-5.41;1.10) for adalimumab to -7.03(-10.34;-3.83) for infliximab in TNFis; and from -1.08(-5.56;3.35) for rituximab to -2.52(-6.36;1.43) for sarilumab in non-TNFis. At 12-months, ACR20 ranged from 62.7%(48.0%;75.9%) for infliximab to 82.5% (56.9%;95.3%) for certolizumab pegol in TNFis; and from 63.6%(41.0%;85.5%) for sarilumab to 73.0%(56.1%;88.3%) for tocilizumab in non-TNFis. CONCLUSIONS: Targeted immune modulator in general showed reduced radiographic progression as measured by mTSS compared with cDMARDs. TNFis appear to be the most effective class as measured by the ACR20.